The influence of a bulky mass on the outcome of DLBCL patients

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INTRODUCTION

In the pre-rituximab era, most (but not all) researchers reported that bulky disease had

an influence on the outcome in patients with aggressive lymphoma and diffuse large

B-cell lymphoma (DLBCL) [1–7]. Divergent results were obtained because of differences

in the patient populations studied. After R-CHOP (rituximab, cyclophosphamide,

doxorubicin, vincristine, and prednisolone) became the standard treatment, the

prognosis of DLBCL with a bulky mass was re-examined. The US Intergroup trial did not

demonstrate that tumor size was an important indicator in DLBCL patients receiving

R-CHOP therapy [8], and bulky disease (a mass 10 cm in diameter) was not identified

as a prognostic factor in the Groupe d’Etude des Lymphomes de l’Adulte (GELA) Study

[9]. However, a recent extrapolative analysis of the MabThera International Trial Group

(MInT) study found a stronger influence of the maximum size of bulky masses on the

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outcome of patients in the rituximab era [10]. Thus, the influence of a bulky mass on the

outcome of DLBCL patients receiving R-CHOP therapy is still unclear[A1].

In patients with a bulky mass, residual tumor is often detected by CT at the end

of treatment, and it is sometimes difficult to determine whether additional treatment

such as radiotherapy should be performed or not. According to the NCCN guidelines

(2013 ver.1), if PET-CT is positive at the end of treatment for limited DLBCL with a

bulky mass (>10 cm), radiotherapy should be considered (Category 1). In patients with

advanced DLBCL and a bulky mass, however whether radiotherapy is required should be

determined on a case-by-case basis (Category 2B).

In the present study, we retrospectively investigated the outcome of DLBCL

patients with a bulky mass and also assessed the accuracy of predicting the prognosis

based on the post-treatment PET-CT findings.

MATERIALS AND METHODS

Bulky disease was defined as a measurable mass 10 cm diameter or a mediastinal mass

>1/3 of the chest diameter [11]. If a bulky mediastinal mass showed invasion of the

surrounding structures and was pathologically diagnosed as DLBCL, the patient was

considered to have primary mediastinal large B-cell lymphoma and was excluded from this

study. From February 2004 to July 2011, 201 consecutive patients who had untreated

DLBCL received R-CHOP therapy (cyclophosphamide 750 mg/m2on Day 1; doxorubicin

50 mg/m2 on Day 1; vincristine 1.4 mg/m2 on Day 1 (max 2 mg); prednisolone 60 mg/m2

on Days 1–5; and rituximab 375 mg/m2 on Day 15) without weight loss[A2]. Among these 201

patients, 29 had a bulky mass. We compared treatment outcomes between the bulky mass

group (n = 29) and the non-bulky mass group (n = 172). We also studied prognostic factors

and the accuracy of predicting the outcome based on detection of residual disease at the end

of R-CHOP therapy in the bulky mass group. The criteria of Cheson et al. were used to

assess the effectiveness of treatment [12] Positron emission tomography-computed

tomography (PET-CT) with 18-F-fluorodeoxyglucose was performed at 6 to 8 weeks after

the completion of R-CHOP therapy[A3]. A negative PET scan was defined as showing no

abnormal uptake or minimal residual uptake. Mediastinal blood pool activity was used

as the reference to define PET positivity. If a residual mass 2.0 cm in greatest

transverse diameter (or a smaller residual mass or normal-sized lymph node) showed

higher uptake than the blood pool, the PET scan was considered to be positive[A4]. All

PET-CT scans were reviewed by a single nuclear medicine physician.

Overall survival (OS) was defined as the interval from diagnosis until death from any

cause or the final date of observation. Progression-free survival (PFS) was defined as the

interval from diagnosis until relapse or progression of lymphoma, death from any cause,

or the final date of observation (if progression or death did not occur). Survival was

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calculated by the Kaplan-Meier method, and differences in survival were assessed by the

log-rank test. The relative risk and its 95% confidence interval (CI) were determined, as

well as P values. All P values were two-sided, with significance being accepted at P0.05.

Statistical analyses were performed with R2.10.1 software (R Foundation for Statistical

Computing, Vienna, Austria[A5]). This study was approved by the institutional review board

of Kanagawa Cancer Center.

RESULTS

Patient profile

The median age of the patients with a bulky mass was 65 years (range: 20–78 years). The

most frequent site of a bulky mass at presentation was the mesenteric lymph nodes

(55%) and the maximum tumor diameter was 11.5 cm (10.0–17.0 cm). The characteristics

of the 29 patients are presented in Table I. The number of patients in stages I, II, III, and

IV was 3, 10, 7, and 9[A6], respectively. There were no significant differences of stage

distribution between the two groups (P=0.625). The International prognostic index (IPI)

risk category was low, low-intermediate, high-intermediate, and high for 6, 10, 8, and 5[A7] of

the patients, respectively. Patients with a bulky were more likely to be in poor risk

categories, though this was not statistically significant (P=0.069). Patients with a bulky

mass were significantly more likely to have a performance status (PS) 2 (45% vs. 19%,

P=0.005), elevation of serum lactate dehydrogenase (LDH) (86% vs. 61%, P=0.007), and B

symptoms (38% vs. 17%, P=0.017).

Outcome of patients with and without a bulky mass

The median follow-up time for surviving patients was 3.2 years (range: 0.7–8.0 years).

Figure 1 shows the 3-year OS and PFS of patients who had limited disease with or

without a bulky mass[A8]. There were no significant differences between the two groups

(90% [95% CI: 84–98] vs. 69% [95% CI: 45–100] [P=0.105] and 83% [95% CI: 75–92] vs.

77% [95% CI: 57–100] [P=0.499], respectively[A9]). Figure 2 shows the 3-year OS and PFS of

patients who had advanced disease with or without a bulky mass. Again, there were no

significant differences between the two groups (76% [95% CI: 67–87] vs. 66% [95% CI:

43–100] [P=0.279] and 72% [95% CI: 63–83] vs. 28% [95% CI: 65–100] [P=0.096],

respectively).

Prognosis of patients with a bulky mass

When prognostic factors for OS and PFS were assessed by univariate analysis, the

findings on post-treatment PET-CT were statistically associated with OS (34% [95% CI:

12–94] for PET-positive patients vs. 75% [95% CI: 43–100] for PET-negative patients

[P=0.014]) and with PFS (36% [95% CI: 18–72] vs. 83% [95% CI: 58–100], respectively

[P<0.001]) (Figure 3 and Table II). In contrast, the age, PS, LDH, stage, and extranodal

disease were not significantly associated with either OS or PFS.

PET-CT was performed before treatment in 27 patients, but not in 2 patients

with rapid disease progression. At the end of treatment, 28 patients underwent PET-CT,

excluding 1 patient with disease progression, and 14 patients had no abnormal uptake of

FDG. Although 5 (2 with limited disease and 3 with advanced disease) of the 14 patients

still had residual tumors on CT, none of them received additional treatment (including

radiation therapy) and all of them remained in remission at the end of the observation

period. The other 14 patients had abnormal FDG uptake at the completion of R-CHOP

therapy. Nine of these patients (3 with limited disease and 6 with advanced disease) still

had a bulky mass on CT, and 5 of them developed recurrence after receiving

radiotherapy[A10].

DISCUSSION

The presence or absence of a bulky mass is not included in the IPI, which is widely used

for predicting the prognosis of DLBCL. However, a poor prognosis has been reported for

DLBCL patients with large extranodal lesions or those with tumors more than 5.0 to 10.0

cm in diameter [10,13,14]. One problem is the lack of a generally accepted definition of a

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bulky mass. In the present study, we defined a bulky mass as a tumor 10 cm diameter or

a mediastinal mass >1/3 of the chest diameter, according to the Cotswolds classification,

which is widely used for clinical staging of malignant lymphoma. As a result, we found

that DLBCL patients with a bulky mass tended to have features that were suggestive of

progressive disease, including a worse PS, B symptoms, a higher serum LDH level, and a

higher IPI risk than in the patients without a bulky mass. However, the presence of a

bulky mass was not correlated with a poor prognosis among patients with either limited

disease or advanced disease.

Among DLBCL patients with a bulky mass before treatment, regardless of

whether or not a residual mass was detected by CT after R-CHOP therapy, those who

were negative for abnormal uptake on PET-CT had a good prognosis without additional

treatment, whereas those with abnormal uptake had a poor prognosis. According to

Juweid et al., about half of the patients with DLBCL achieving PR on post-treatment CT

showed no uptake of FDG, and their progression-free survival was almost equivalent to

that of CR patients without additional treatment and was better than that of patients

with FDG uptake[15]. There have been few reports about the outcome of DLBCL with a

bulky mass based on post-treatment PET-CT findings. Our results suggested that

performing PET-CT at the end of R-CHOP therapy may be useful for predicting the

prognosis, similar to the case for DLBCL without a bulky mass.

However, the positive predictive value of PET-CT is not so high, since judgment

of positive uptake is difficult and poor reproducibility of assessment between interpreters

has been pointed out. Although we used the efficacy criteria proposed by Cheson et al., a

five-point scale has recently been employed in clinical trials with interim PET and the

usefulness of this scale has been reported [16]. Therefore, the criteria for assessing

efficacy should be studied further and standardization of the criteria for PET-CT

positivity should be a target for the future.

Radiotherapy for residual lesions did not seem to be important in our patients

who showed no uptake on post-treatment PET-CT at the end of R-CHOP therapy.

However, the present study was not designed to assess the usefulness of radiotherapy,

emphasizing the need for additional clinical studies.

In conclusion, the present study demonstrated that a bulky mass was not a poor

prognostic indicator for patients with DLBCL. Instead, the results of PET-CT at the end

of treatment may be useful for predicting the prognosis. Although our study had the

limitations of a retrospective design and a small number of subjects, the results

suggested that radiotherapy may not be required for a residual bulky mass if there is no

abnormal FDG uptake on PET-CT at the end of R-CHOP therapy. However, confirmation

by a prospective study is needed.

There was no funding for this study.

Potential conflict of interest

The authors have no conflict of interest to declare.

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Figure legends

Figure 1. Overall survival of all patients. (A) Limited disease. (B) Extensive disease.

Figure 2. Progression-free survival of all patients. (A) Limited disease. (B) Extensive

disease.

Figure 3. Overall survival and progression-free survival of patients with a bulky mass

stratified by post-treatment PET-CT findings. (A) Overall survival. (B) Progression-free

survival.


[A1]The literature review is not extensive.include more recent studies.

[A2]Was any dose modification used in these patients based with poor PS.

Was any CNS prophylaxis used in the treatment protocol

[A3]What were the time points when PET-CT was done. Was the PET CTdone initially and during interim evaluation.

[A4]Was Delta SUV taken into account while defining PET positivity. What quality standards used in the study while doing the PET-CT?

[A5]Which statistical test used to analyse nivariate analysis? Was COX regression model used in the analysis

[A6]Use percentages in parenthesis also.

[A7]Use percentages in parenthesis also.

[A8]Check the order of the data. It should have been without and with bulky mass.

[A9]The survival for advanced stage DLBCL and localized DLBCL is is high ,not matching the literature review. What could be the reasons for this improved survival?

[A10]Nine patients had bulky PET positive disease at completion of therapy. Was the re biopsy done prior to giving radiotherapy? According to present guidelines these patients should have received some form of salvage therapy along with autologous transplant & radiation.